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Transcription

Patient case presentation

I will present the case of a lorry driver. He is a heavy goods vehicle driver. He is a bit of a loner, he’s a single man. He lives for his work, believe it or not. He drives cargo to Europe and back and his priority is to keep on working.

Full transcription

Full transcription

Patient case presentation

I will present the case of a lorry driver. He is a heavy goods vehicle driver. He is a bit of a loner, he’s a single man. He lives for his work, believe it or not. He drives cargo to Europe and back and his priority is to keep on working.

Patient case presentation

He was diagnosed with locally advanced prostate cancer some 13 years ago and treated with hormones and radiotherapy initially. He relapsed very quickly. At this point I should emphasise that I was not looking after him, so feel free to criticise his management.

Patient case presentation

He had bicalutamide monotherapy for PSA failure and when he progressed biochemically he was then switched to an LHRH agonist.

We are now about seven years after his radiotherapy and he has become castrate refractory. He has a rising PSA whilst on his LHRH agonist and no evidence of metastases.

Patient case presentation

Now he was managed – not by me – by observation. He was observed for some considerable time with a rising PSA while still on an LHRH analogue alone, so I would not advocate this.

Now in 2011, he developed metastatic disease. On a bone scan, small volume bone metastases. CT at this time showed no evidence of disease elsewhere.

Now one question that arises is about the definition of symptomatic. So was this man symptomatic or was he not?

Well he certainly had low back pain. In fact he had had low back pain for 20 years. He was taking paracetamol from time to time, so in that sense he was definitely symptomatic but it’s unlikely I would say that his symptoms were coming from metastatic prostate cancer – impossible to be sure.

Patient case presentation

He was managed – not by me – using stilboestrol, something I would positively recommend against. Now obviously it’s active and he stayed on it for over a year, but it has in my view a completely unacceptable toxicity profile with a significant risk of thrombosis which occasionally is actually fatal, so for that reason I would never use stilboestrol in this situation.

When he progressed biochemically he was then switched to dexamethasone which is not at all unusual in the UK.

And then when he progressed biochemically on dexamethasone about six months later he then started abiraterone.

Patient case presentation

He responded to abiraterone for about six months and then this is when I took over so now you be careful when you are criticising now.

He came to me with a rising PSA, small volume bone metastases, possibly symptomatic, possibly not symptomatic.

Patient case presentation

He entered the PROSPECT trial, so a placebo-controlled trial of PROSTVAC.

And he completed the course of treatment, five months of treatment in the PROSPECT trial.

Patient case presentation

At the end of which he remained well, performance status of zero, he is still working full-time driving his lorry to Europe.

He still has a bit of low back pain as he has done for 20 years, he’s still taking paracetamol. His bone metastases have become a bit more prominent as you can see and he has no evidence of visceral or nodal disease on CT.

So I treated him with radium-223 and he received six cycles from April last year.

Patient case presentation

And a few things about what happened to him during his treatment with radium. First of all at baseline, prior to radium he had a rather low platelet count. He had a platelet count of about 110 and this was a slight concern for me because I know that radium treatment does have a risk of thrombocytopenia, about a 5% rate of Grade 3 or 4 thrombocytopenia and I thought this gentleman was more at risk than the average.

But in actual fact his platelets fell to 86 to be precise and then remained roughly stable throughout the subsequent six months of treatment, so my concern there was not well founded.

What about his PSA? Prior, immediately prior to treatment with radium when he attended on the day of his first radium treatment, his PSA was about 150, so four weeks later when he was coming for cycle two, his PSA had more than doubled. It was nearly 400, so any of you would still be acting on PSA alone would I guess be thinking about stopping his radium, but I’ve used radium for 11 years now. I know not to expect PSA changes in response to radium and I carried on.

In fact the only surprising thing to me is that his PSA subsequently fell during radium. This is actually quite unusual and you can see his PSA fell month on month throughout his treatment with radium, although at the end of treatment after six months it was still higher than at baseline. So do not be over-concerned about a rising PSA during treatment with radium. It is the norm. It’s very unusual indeed to get a PSA response during treatment with radium-223.

We know the drug works, we know it improves survival by 30%, we know it improves quality of life, we know it delays symptomatic skeletal events; just don’t expect much change in PSA.

What you do often get, in fact almost always is a significant decline in alkaline phosphatase and you can see his alkaline phosphatase was elevated at baseline and then fell substantially and that’s really to be expected.

So here is data from the ALSYMPCA trial looking at changes in serum alkaline phosphatase comparing radium versus placebo and you can see a really profound difference with dramatic declines in patients treated with radium-223 that interestingly persist some six months after treatment.

What this means, I don’t know. Does it reflect a direct cytotoxic effect on the cancer? Does it reflect some change in bone physiology? We don’t know.

ALP decline at 12 weeks (confirmed) is associated with outcome

What we do know is if you look within patients treated with radium, so this is not the placebo, just patients treated with radium that those men who do get a significant decline in alkaline phosphatase do better in terms of survival than those men who don’t get a significant decline in alkaline phosphatase.

That’s not to say that it’s the alkaline phosphatase that makes the difference. It could just be that the former patients are destined to do better anyway, and in any case the vast majority of patients treated with radium do get a significant decline in alkaline phosphatase; it is quite unusual not to.

Patient case presentation

At the end of treatment with radium he still had his low back pain just like he had done for the last 20 years and he liked the treatment, he tolerated it without any adverse effects, he carried on working full-time. In fact the one thing he did point out to me is that once he was caught at the barrier when he was trying to get in to Europe because he triggered a radiation alarm as he drove his truck the day after treatment. Obviously very sensitive radiation alarms.

Patient case presentation

He finished treatment about a year ago and I actually saw him just two days ago – before I come to that, what about imagine? I don’t routinely image my patients during treatment with radium, but this chap happened to have a CT scan at the end of treatment and it was typical in so far as it showed very dense sclerosis in the sites of his bone disease.

So again I don’t know what that means, but that’s typical. We’ll hear what Francis has to say later. I don’t think one can use CT scan usefully to monitor response to radium. I do tend to do CT scans if I’m getting very worried about the rate of rise of PSA if I suspect he might have developed visceral disease and I’ll do a CT scan to rule out visceral disease, but not to look at the bones.

Patient case presentation

That just summarises his PSA kinetics which, as I say are unusual in so far as he had a significant change in his PSA whilst on treatment with radium.

Patient case presentation

I saw him just this week. Since he has had his radium, he has been treated with enzalutamide to which he responded but not for terribly long and he is now still well, still working full-time but has a rising PSA and he has just started his first re-treatment with radium-223, so we’ll see how he gets on the second time round.

Thank you very much. [Applause]

Maria De Santis: Thank you, Chris. Would you like to come back? I have a few questions to you. It was a great case and you indicated and you showed impressively that PSA actually does not change and PSA is of no particular use for decision-making in patients on radium-223.

But now what about alkaline phosphatase? Actually it should decline, right but what would you do if alkaline phosphatase would rise and maybe PSA was stable?

Christopher Parker: So as I said it’s extremely unusual for the alkaline phosphatase to rise during treatment with radium-223. I can’t recall in all my 11 years of using radium-223 ever coming across the scenario you have just described of a rising alkaline phosphatase and a stable PSA.

What would I do in that situation? I guess I would keep going. I mean, the schedule that was shown to be well tolerated and effective was to treat with six cycles and so that is my norm, I usually treat for six cycles.

I think the significance of the alkaline phosphatase is uncertain. We don’t really know why the alkaline phosphatase changes so dramatically but it usually does.

Maria De Santis: So then alkaline phosphatase usually does not rise, alright, but if the patient had for example an imaging showing progression in the nodes or in the liver, would you just add something or change treatment completely?

Christopher Parker: So if the imaging showed progression in the nodes, then my first reaction would be to change his hormonal treatment but keep going with the radium, so change dex to abi or abi to enza, whatever was the most appropriate hormonal manoeuvre but continue with the radium.

If he developed visceral disease, then I think I would say ‘Well hang on, we don’t have data for using radium in the context of visceral disease’, so I think I would stop the radium and switch to something entirely different.

Maria De Santis: Alright. A further question then to Francis; would you use any imaging to show a response to radium-223, any studies about that, any thoughts about that?

Francis Sundram: If we just go back to the case here and the point, I think this chap had back pain for many years and I just wondered if anybody did a plain film in the first instance just to rule out if he had any significant degenerative change. That would be something probably easy to do and readily available.

And certainly in terms of further assessment, because his bone scans were pretty much stable-ish or normal-ish, I think certainly in terms of an MRI maybe of the spine might have been helpful in terms of trying to see what’s happening in the spine. It probably would be I think reassuring in terms of ‘Yes, this is probably degenerative change’. It’s very unlikely, like you said, to be metastatic disease in the context of his long history.

Sorry Maria, to come back to your question about whether in radium treatment we routinely image. Now certainly in ALSYMPCA bone scans were not routinely performed, so there’s no precedent that one should do a bone scan during treatment and like Chris, in our practice we don’t routinely image patients once they are on treatment.

I guess you probably would be guided by symptoms. If the patient is complaining of localised pain, you might wish to do a localised plain film, localised CT and take it from there but I think the important thing is to put the clinical, the biochemical and the imaging parameters together and then to take your decision-making process forward.